2'-O-{3-[methyl(4-quinolinylmethyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A | 1104201-35-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2'-O-{3-[methyl(4-quinolinylmethyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
• 英文别名: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[3-[methyl(4-quinolylmethyl)amino]propoxy]tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one；(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[3-[methyl(quinolin-4-ylmethyl)amino]propoxy]oxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one
• CAS: 1104201-35-5
• 化学式: C₅₂H₈₈N₄O₁₂
• 分子量: 961.29
• InChiKey: PKTHHOYUOFMCDM-YHCWBMTKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  68
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  185
• 氢给体数：
  4
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  阿奇霉素 在 甲醇 、 4-二甲氨基吡啶 、 platinum(IV) oxide 、 甲酸 、 水 、 氢气 、 sodium hydride 、 溶剂黄146 、 三乙胺 、 lithium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 氯仿 、 mineral oil 、 叔丁醇 为溶剂， 60.0 ℃ 、500.01 kPa 条件下， 反应 213.0h， 生成 2'-O-{3-[methyl(4-quinolinylmethyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
  参考文献：
  名称：

  Design, Synthesis, and in Vitro Activity of Novel 2′-O-Substituted 15-Membered Azalides

  摘要：

  Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2'-O-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2'. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.

  DOI：

  10.1021/jm201676t

文献信息

• Compounds
  申请人：Alihodzic Sulejman

  公开号：US20090036388A1

  公开（公告）日：2009-02-05

  The present invention relates to novel 2′-O-substituted 9-deoxo-9 a -methyl-9 a -aza-9 a -homoerythromycin A derivatives having antimalarial activity. More particularly, the invention relates to 2′-O-substituted-9-deoxo-9 a -methyl-9 a -aza-9 a -homoerythromycin A and 2′-O-substituted-3-O-decladinosyl-9-deoxo-9 a -methyl-9 a -aza-9 a -homoerythromycin A derivatives having antimalarial activity, to the intermediates for their preparation, to the methods for their preparation, to their use as therapeutic agents, and to salts thereof having antimalarial activity.

  本发明涉及具有抗疟活性的新型2'-O-取代的9-去氧-9a-甲基-9a-氮-9a-同异红霉素A衍生物。更具体地，本发明涉及具有抗疟活性的2'-O-取代-9-去氧-9a-甲基-9a-氮-9a-同异红霉素A和2'-O-取代-3-O-去氧-9-去氧-9a-甲基-9a-氮-9a-同异红霉素A衍生物，以及它们的制备中间体、制备方法、用作治疗剂的用途以及具有抗疟活性的盐。
• Design, Synthesis, and in Vitro Activity of Novel 2′-<i>O</i>-Substituted 15-Membered Azalides
  作者：Dijana Pešić、Kristina Starčević、Ana Toplak、Esperanza Herreros、Jaume Vidal、Maria Jesus Almela、Dubravko Jelić、Sulejman Alihodžić、Radan Spaventi、Mihaela Perić

  DOI：10.1021/jm201676t

  日期：2012.4.12

  Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2'-O-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2'. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.